New derivatives of 1,4-benzodioxan, the preparation and the use thereof

ABSTRACT

This invention relates to new derivatives of 1,4-benzodioxan, namely 2-(N-(R1, R2-aminoalkyl or aminoalkanoyl)-N-phenyl or 2pyridyl aminomethyl)-1,4-benzodioxans, in which R1 is hydrogen or a lower alkyl radical and R2 is a lower alkyl radical, whereby R1 and R2 may also form with the attached nitrogen atom a nitrogenous heterocyclic ring, as well as the acid addition salts of said new derivatives. The new compounds are valuable therapeutic agent for the treatment of heart arrhythmy.

i United State atet 11 1 Vanhoof et al.

[ Nov. 4, 1975 NEW DERIVATIVES OF 1,4-BENZODIOXAN, THE PREPARATION AND THE USE THEREOF Inventors: Pierre M. Vanhooi; Pierre M.

Clarebout, both of Brussels, Belgium A. Christiaens, Societe Anonyme, Brussels, Belgium Filed: Sept. 25, 1973 Appl. No.: 400,605

Assignee:

Foreign Application Priority Data Septv 26, l972 United Kingdom 44435/72 US. Cl 260/296 B; 424/263; 424/267; 424/274; 260/293.58; 260/326.36; 260/326.5 D

Int. CL C07D 211/26; C07D 213/46 Field of Search 260/340.3, 296 B, 293.58, 260/326.36, 326.5 D

References Cited UNITED STATES PATENTS 11/1954 Swain 1260/3403 X 2,695,295 11/1954 Swain 260/340.3 X 2,725,386 11/1955 Bovet 61:11 260/340.3

FOREIGN PATENTS OR APPLICATIONS 1,005,028 9/1965 United Kingdom 260/340.3

OTHER PUBLICATIONS Banziger et al., J. Am. Pharm. Assoc. Vol. 44, pp. 302 to 305 (1955).

Primary Examiner-John D. Randolph Attorney, Agent, or Firm-Sughrue, Rothwell, Mion, Zinn & Macpeak [57] ABSTRACT The new compounds are valuable therapeutic agent for the treatment of heart arrhythmy.

11 Claims, N0 Drawings NEW DERIVATIVES OF 1,4-BENZODIOXAN, 1 I:

PREPARATION AND THE USE THEREOF SUMMARY OF THE INVENTION in which n l or 2, X represents two hydrogen atoms or one oxygen atom, R and R represent a lower alkyl group containing 1 to 4 carbon atoms or form together with the attached nitrogen atom a nitrogenous heterocyclic ring, with the priviso that R may also represent hydrogen and A represents a phenyl or 2-pyridyl group, as well as the acid addition salts of said compounds of formula (I).

This invention relates therefore also to pharmaceutical compositions containing, as active ingredient, at least one compound of the general formula I, together with a pharmaceutically acceptable carrier.

This invention relates also to processes for preparing the compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION The preferred compounds of the formula I are those in which R and R represent a methyl, ethyl, propyl or isopropyl group and those in which R represents hydrogen and R represents a methyl, ethyl, propyl or isopropyl group, as well as the acid addition salts thereof, such as the hydrochlorides, furmarates, etc.

The new compounds according to this invention have interesting pharmacological properties. They can be used for the treatment of heart arrhythmia.

It has surprisingly been found that the components of the general formula I are very active for the treatment of heart arrhythmia.

Said compounds can be used for the treatment of various heart diseases such as premature heart contractions, ventricular and surpraventricular tachycardias either idiopathic or subsequent to a cardiopathia or to a coronary disease, cardiac arrhythmias due to digitalin intoxication, as well as atrial fibrillation and flutter, particularly in the early stage.

It is known (see KochWeser, J. Arch. Int. Med. 129; 763, 1972) that none of the presently available antiarrhythmic agents are satisfactory for the prophylaxis of tachycardias and fibrillation of ventricular origin.

The oral activity of the known antiarrhythmic agents,

such as procainamide or lidocaine, is either too short practical utility (for example with lidocaine) of their therapeutic activity is conjugated with frequent and dangerous side effects, such as hypotension (with procainamide), sudden death, agranulocytosis or idiosyncrasy.

The compounds of general formula I according to this invention are very active when orally administered, although they may also be administered parenterally. They have also a long activity duration and are not depressant for the myocardial function.

Applicants do not known any orally active antiarrhythmic agent which does not act at the same time as a depressant of the myocardial function.

The oral antiarrhythmic activity of the compounds of formula I has been proved by tests on rats using aconitine which is a compound causing premature heart contractions and death of the animals.

The method used for these tests is described hereafter:

Animals Male or female rats with a body-weight ranging from 380 to 450 g.

Aconitine solution 3.12 ug aconitine nitrate/l ml physiological saline.

Solution of the compound to be tested 0.75 in distilled water.

Method Six random selected animals are required for each compound to be tested. The compound is administered by oral route at the dose of mg/kg (1 ml of the 0.75 solution/ g of body weight) 75 minutes before the intraveinous perfusion of the aconitine solution is initiated. Control groups of animals are treated only with distilled water (1 ml/lOO g).

Sixty minutes after the administration of the compound to be tested, the animals are anesthesized by an intraperitoneal injection of Pentobarbital (50 mg/kg) and the jugular vein is dissected.

A catheter is introduced in the vein and fixed by a ligature. The ECG (D II derivation) is then continuously recorded. The perfusion of the aconitine solution is started 75 minutes after the administration of the compound to be tested. The volume delivered by the injection device being 0.287 mg/minute, the dose of aconitine nitrate administered is 0.895 ,ug/minute (0.20 0.24 ,ug/ l 00 g/min. according to the minimal and maximal weight of the animals). The experience is stopped as soon as the first extrasystoles are appearing and the time elapsed from the beginning of the perfusion is noted. The results are expressed as the mean total dose of aconitine injected in a group of animals.

The relative activity between a tested compound and a reference substance (lidocaine, procainamide) is computed in the following way:

where A (x) activity of tested compound X (in Y= mean dose of aconitine in the animals treated by compound X C mean dose of aconitine injected in the untreated an i mals (controls) R mean dose of aconitine injected in the animals treated by the reference substances.

The following table gives the results of the evaluation of the antiarrhythmic activity by oral route of a great number of acid addition salts of compounds of formula I compared to the activity of two well known antiarrhythmic agents (procainamide and lidocaine).

TABLE in which A has the above meaning.

According to this invention, the compounds of formula I may be prepared by a first process involving the following steps:

1. Reaction of a 2-(A-aminomethyl)1,4-benzodioxan of the formula (II) with sodium amide so as to obtain the sodium salt of said compound of formula (II);

2. Reaction of the sodium salt of the compound of formula (II) with a halogenated amine of the formula:

The compounds of the formula I may be administered orally or parenterally.

Oral preparations may be administered under the form of capsules, tablets, pills and the like. Each capsule, tablet or pill may contain from to 200 mg of a compound of formula I as active ingredient, together with pharmaceutically acceptable excipients or carriers.

Parenteral preparations may consist in a solution for perfusion or for intraveinous or intramuscular injection. Such a solution may contain 0.2 per thousand to 2 per thousand of a compound of formula I.

The parenteral preparation may be either a solution which may be directly used for the perfusion and contains a proportion of the active ingredient within the above limits, or a concentrated solution containing 1 to 10 of the active ingredient, said concentrated solution being diluted when administered to a patient.

The initial dose of active ingredient may be of 200 to 800 mg per day during 2 or 3 days, the maintenance dose being of about mg to 300 mg per day.

If a single dose is sufficient for obtaining the therapeutic effect, this dose is generally comprised between 50 and 300 mg.

The active ingredient may be administered at the same time by the parenteral route (for example by perfusion) and by oral route.

In the various processes according to this invention described hereinafter, the compounds of formula I are prepared from a 2-( A-aminomethyl)-1,4-benzodioxan of the following formula:

(III) \R2 1. Acylation of a 2-(A-aminomethyl)-l,4-benzodi- I oxan of the formula (II) by means of a chloride of a halogenated aliphatic acid of the formula:

Hal(CI-I COCI (IV) in which Hal represents a halogen atom and n l or 2, so as to obtain a 2-((N-haloalkanoyl-N-A- aminomethyl)-1,4-benzodioxan of the formula:

CO-(CH2),,, Hal

0 CH2-N 2. Reaction of the 2-(N-haloalkanoyl-N-A-aminomethyl)-l,4-benzodioxan of the formula (V) with an amine of the formula:

formula (II) may be prepared. from a 2-hydroxymethyl- HN (VI) l,4-benzodioxan of the formula:

\ z I 5 o /CH2OH in which R and R have the above meanings, so as to l (X) obtain a N-alkylated derivative of the following formula: o

CH,N 2

The compound of formula (X) may be prepared by known methods described by .1. K00, S. Avakian and means of lithium aluminum h dride (AlLiI-I in ether Martm m 5373 (1955) or by so as to obtain a compound of the formula (I), wherein and De March m TETRAHEDRON 1962 X 18, pages 289 298.

The method for obtammg a 2-(N-A-ammomethyl)- 1,4-benzodioxan of the formula (II) from a 2-(N-A- aminomethyl)-1,4-benzodioxan of the formula (II) from a Z-hydroxymethyl-l,4-benzodioxan of the formula (X) involves the following steps:

1. Reaction of Z-hydroxymethyl-l,4-benzodioxan of the formula (VIII) with the methane sulfonic acid chloride, so as to obtain the mesylate of Z-hydroxymethyl- 1,4-benzodioxan of the formula:

3. Reduction of the compound of formula VII by The amine of formula (VI) used in the second step of the above process may be a primary of secondary amine.

A primary amine of the formula H NR is used, when 30 a compound of the formula (I), in which R represents hydrogen whereas R represents a lower alkyl group has to be prepared.

A secondary amine of the formula cmoso cn H N R2/ l o 40 is used, when a compound of the formula (I) in WhlCh R and R each represent a lower alkyl group or form together with the attached nitrogen atom a heterocy- 0 clic nitrogenous ring, such as morpholino, piperidino, pyrrolidino 0r piperazino g, has to be p p 2. Reaction of the mesylate of formula (XI) with ani- According to this invention, the compounds of forli or L i idi so as to b i h 2 -A mula y also be P p y a third Process aminomethyl)-l,4-benzodioxan of the formula (II). volving the following steps 1. Reaction of a Z-(A-aminomethyU-l,4-benzodi- EXAMPLES oxan of the formula (II) with adihalogenated hydrocar- Th E l 1 to 15 ill th preparation f bOn 0f the formula compounds of formula (I).

Br-(CI-I m Cl (VIII) EXAMPLE 1 Preparation of the fumarate of n 1 or so as to obtain a compound of the 2-[N-(y-diethylaminopropyl)-l I-phenylaminomethyl]- 1 ,4-benzod1 oxan (CHQFG a. Preparation of mesylate of 2-hydroxymethyl-l,4-

benzodioxan (formula IX). 0 6.9 grams (0.041 mole) of 2-hydroxymethyll ,4-benx zodioxan are dissolved in 6.9 grams of anhydrous pyridine. The solution is cooled to 0C. 5.61 grams (0.049

mole) of mesyl chloride are then added drop by drop 0 within 20 minutes, while maintaining the temperature at 0C during the addition. The reaction mixture is then allowed to return to the room temperature and is mixed 2. Reaction of the obtained compound of the formula at this temperature during 30 minutes. The mixture is (IX) with an amine of the formula (VI). then poured on ice and extracted with ether. After dry- The 2-(N-A-aminomethyl)-l,4-benzodioxans of the ing of the ether extracts on magnesium sulfate, the

7 ether is evaporated. 9.5 grams of mesylate are obtained. The product is recrystallized from ether; M.P. 5354C.

'8 propyldiethyl-amine and hydrochloric acid instead of fumaric acid, the desired hydrochloride is obtained. This compound melts at 143'144C after recrystallization from benzene.

Analysis: C H S calculated: 49.18 4.95 13.10 7 Analysis: vC H Cl found: 49.0 4.8 13.25

calculated: 66.91 7.75 7.43 9.4 found: 66.90 6.80 7.55 9.46 b. Preparation of 2-(phenylaminomethyl)-1,4-benzodioxan (formula 11 A phenyl) 9.5 grams of the mesylate (0.04 mole) and 14.9 EXAMPLE 3 grams (0.16 mole) of aniline are mixed and gradually Prepara i n of t hydrochloride Of heated to 150C this temperature being maintained -(vy p py -p y during minutes. A precipitate of aniline mesylate is formed. After cooling and addition of ml of ether, the aniline mesylate is filtered off. This ether is then removed from the filtrate and the excess of aniline is distilled. By distilling the residue, 7.4 grams (yield 77%) of on oil distilling at 163C (0.3 mm) are obtained.

Since this oil does not crystallise, it is dissolved in 50 ml of anhydrous ethanol, whereafter a stream of dry hydrochloric acid is passed through the obtained solution.

zodioxan (formula 1; R R C H n 2, X H A phenyl) 6 grams (0.025 mole) of 2-(phenylam nomethyl)-1,4- benzodioxan, 1.87 grams (0.048 mole) of sodium amide and 125 ml of anhydrous benzene are stirred during 15 minutes under a nitrogen atmosphere and then refluxed during 30 minutes. 5.98 grams (0.04 mole) of 'y-chloropropyldiethylamine are then added and the mixture is refluxed during 21 hours. After cooling, the reaction mixture is poured on ice and the benzene phase is decanted. This benzene phase is then extracted by means of 1 N hydrochloric acid (50 ml). The obtained solution is made alkaline by means of ammonia, so as to release 6.98 grams of the desired amine which is extracted by means of 2.28 grams of fumaric acid and 100 ml of water. The solution obtained at 60C is evaporated to dryness. The obtained residue is recrystallised from isopropanol. 8.44 grams of the fumarate are obtained. Melting point: 138 140C Preparation of the hydrochloride of 2'[N-(B-diethylaminoethyl)-N-phenylamimomethyl]- X H A phenyl) .Byusing the process described in example 1, section C, using B-chloroethydiethylamine instead of y-chlorothyl]-1,4-benzodioxan (formula 1: R R CH n 2; X H A phenyl).

By using the process described in example 1, section C using 'y-chloropropyldimethylamine instead of 'ychloropropydiethyl-amine and hydrochloric acid instead of fumaric acid, the desired hydrochloride is obtained. This compound melts at 132134C after recrystallization from acetone.

The obtained hydrochloride is puified by crystallization 25 from angydrous ethanol. Melting point: 191 193C.

.- l Analysis C H N C] calculated: 66.19 7.49 7.71 9.76 7 Analysis: C H N Cl found: 66.26 7.31 7.74 9.81

% calculated: 65.1 5.46 5.05 12.81 30 found: 6497 5.78 5 4 12.72

EXAMPLE 4 (c. Preparation of the fumarate of Z-[N-(y-die- P f of the oxalate of thylaminopropyl)-N-phenylaminomethyl 1 ,4-ben- 35 'l '('Y' P Py P P 'P y thyl]-l ,4-benzodiaxan (formula 1: R R -C H n 2; X H A phenyl) By using the process described in example 1, section C using y-chloropropyldipropylamine instead of ychloropropyldiethylamine and oxalic acid instead of fumaric acid, the desired oxalate is obtained. This compound melts at 109-11 1C after recrystallization from a mixture of acetone and ether.

H A phenyl) By using the process described in example 1, section C using B-chloroethyldimethylamine instead of 'ychloropropyldiethylamine and hydrochloric acid instead of fumaric acid, the desired hydrochloride is obtained. This compound melts at 167l70C after recrystallization from a mixture of acetone and methanol.

Analysis: C H N C1 calculated: 65.41 7.22 8.02 10.16 65.65 7.22 8.05 10.18

% found:

EXAMPLE 6 Preparation of the hydrochloride of 2-[N-( B-piperidinoethyl)-N-phenylaminomethyl]- l ,4- benzodioxan (formula 1 I piperidino; \R I Analysis: C H N Cl calculated: 67.94 7.51 7.20 9.11

% found: 68.14 7.42 7.20 9.31

EXAMPLE 7 Preparation of the hydrochloride of Z-[N-(B-pyrrolidinoethyl)-N-phenylaminomethyl]-1,4-

benzodioxan (formula I l pyrrolidine; I

By using the process described in example 1, section C using N-B-chloroethylpyrrolidine instead of ychloropropyldiethylamine and hydrochloric acid instead of fumaric acid, the desired hydrochloride is obtained. This compound melts at 168-l70C after recrystallization from benzene containing a small amount of ethanol.

Analysis: C H N Cl calculated: 67.27 7.25 7.47 9.45

% found: 67.46 7.26 7.41 9.54

EXAMPLE 8 Preparation of the hydrochloride of 2- N-( ethylaminoacetyl )-N-phenylaminomethyl ]-1 ,4- benzodioxan (formula I: R H; R C H X O; n =1, A phenyl) a. Preparation of 2-[N-chloroacetyl-N- phenylaminomethyl]-l,4-benzodioxan (formula V: n' 1; Hal Cl; A phenyl) 1 mol of 2-(phenylaminomethyl)-l,4-benzodioxan (formula II) and 1.5 mols of chloroacetyl chloride are heated to the boiling temperature during 4 hours in 2.4 liters of benzene.

The solvent and the excess of the reagents is then evaporated. The oily residue is directly used in the following step.

b. Preparation of the hydrochloride of 2-[N- (ethylamino-acetyl )-N-phenylaminomethyl 1 ,4-benzodioxan 10 g. of the compound obtained in section (a) of this example and 52.6 g of a 21% alcoholic solution of eth-' ylamine are heated in an autoclave during 24 hours at 110C. After cooling, the reaction medium is evaporated to dryness, ml of 1 N coustic soda are added to the residue and the obtained solution is extracted by means of chloroform. The chloroform phase is dried on potassium carbonate. After removal of the solvent, the residue is treated with ml of anhydrous ether and a stream of dry hydrochloric acid is bubbled in the ether solution at 0C. A white solid precipitates. From the ether phase, a further amount of the desired product is recovered. By recrystallizing the solids from a mixture of acetone and methanol, the desired product melting at 188189C is obtained.

Analysis C H N Cl calculated 62.89 6.38 7.72 9.77

% found 62.69 6.34 7.54 9.88

EXAMPLE 9 Preparation of the hydrochloride of 2-[ N-( methylaminoac etyl )-N-phenylaminomethyl 1,4-benzodioxan (formula 1: R H; R CH X 0,n l, A phenyl) Analysis C H N Cl calculated 2 61.97 6.07 8.03 l0. l7

% found EXAMPLE 10 Preparation of the hydrochloride of 2-[N-(,B-diethylaminopropionyl)-N-pheny1aminomethyl]- l ,4-benzodioxan (formula I: R R C H X n 2; A phenyl) a. Preparation of 2-[N-(B-chloropropionyD-N- phenylaminomethyl]-1,4-benzodioxan (formula V: n 2, Hal Cl A phenyl).

This compound is prepared as described in example 8, section a, except that ,B-chloropropionyl chloride is used instead of chloroacetyl chloride. After recrystallization from petroleum ether (40'60C), the desired compound melts at 71-72C Analysis 1 C H N Cl calculated 65.16 5.46 4.21 10.61 found 65.25 5.40 4.17 10.77

Analysis C H N Cl calculated 65.25 7.21 6.91 8.75 found 64.72 7.12 7.41 9

EXAMPLE 11 Analysis C H N Cl calculated 63.73 6.68 7.43 9.4

% found 63.98 6.76 7.39 9.52

EXAMPLE 12 Preparation of the hydrochloride of 2-[N-(methylaminopropionyl)-N-phenylaminomethyl]- l ,4-benzodiox'an (formula 1: R H; R CH n 2, X 0; A phenyl) By using the method described in example 10, sections a and b, except that a 33 alcoholic solution of methylamine is used, the desired hydrochloride melting at 142-l45C after recrystallization from acetone is obtained.

Analysis C H N Cl calculated 62.89 6.38 7.71 9.77

% found 62.26 6.21 7.71 9.86

EXAMPLE 13 Preparation of the hydrochloride of 2-[ N-( y-ethylaminopropyl )-N-phenylaminomethyl 1,4-benzodioxan (formula I: R, H; R C H n 2; X H A phenyl) a. Preparation of 2-[N-('y-chloropropyl)-N- phenylaminomethyl]-1,4-benzodioxan (formula IX: 11 3; A phenyl) 3.3 g. of 2-phenylaminomethyl-1,4-benzodioxan and 3 ml of 1.3-chlorobromopropane are stirred during 24 hours at C. After removal of the excess of 1,3- chlorobromopropane, an oilyresidue is obtained.

b. Preparation of the hydrochloride of 2-[N-('yethylaminopropyl)-N-phenylaminomethyl]- l ,4-benzodioxan The product obtained in section a is heated during 24 hours in an autoclave at l 10C together with an excess of ethylamine and ethanol.

The method used in example 8, section b, is then used. The obtained hydrochloride melts at l14l 16C after recrystallization from acetone.

Analysis C H N Cl calculated 66.19 7.49 7.71 9.76 found 65.95 7.34 7.58 9.72

EXAMPLE 14 Preparation of the oxalate of 2-[N-(y-methylaminopropyl)-N-phenylaminomethyl]- 1,4-benzodioxan (formula 1: R H; R CH X H 11 2; A phenyl) a. First method.

This compound is prepared by reaction of 2- phenylaminomethyl-l,4-benzodioxan with 'y-bromopropylmethylamine in the presence of an excess of sodium amide using the method described in section a of example 1. 0.5 mol of 2-phenylaminomethyl-l,4-benzodioxan and 2.5 liters of benzene are introduced in a reaction vessel under an atmosphere of nitrogen. 0.95 mol of sodium amide are added and the mixture is stirred during 3 hours at room temperature 0.8 mol of 'y-bromopropyl-methylamine are then quickly added. After agitation during 1 hour at room temperature, the reaction mixture is refluxed and stirred under nitrogen during 21 hours. The mixture is then allowed to cool and poured onto ice. The obtained aqueous phase is extracted by means of benzene. The benzene extract is washed with water and the benzene is evaporated.

The residue is treated with oxalic acid in a known manner. The obtained oxalate melts at l45l48C after recrystallization from a mixture of acetone and methanol.

b. Second method.

The same compound is prepared by reduction of 2 [N-(methylaminopropionyl)-N-phenylaminomethyl]- 1,4-benzodioxan by means of lithium aluminum hydride in ether.

A solution of 45 g of 2-[N-(methylaminopropionyl)- N-phenylaminomethyl]-1,4-benzodioxan in 1000 ml of ether is added drop by drop to a mixture of 500 ml of ether and 8.7 g of lithium aluminium hydride at room temperature. After this addition, the reaction mixture is refluxed during 2 hours.

By extraction by means of ether, a product is obtained which is converted into the desired oxalate.

EXAMPLE Preparation of the oxalate of 2- N-( 'y-diethylaminopropyl )-N-( 2-pyridyl 1 ,4-benzodioxan (formula I: R R C l-l X H n 2, A =2-pyridyl) Analysis C H N Cl calculated 60.32 5.42 10.04 12.71 found 60.42 5.48 9.73 12.60

b. Preparation of the oxalate of 2-[N-(y-diethylaminopropyl )-N-( 2-py ridyl l ,4-benzodioxan This compound has been prepared by the method described in section C of example 1.

The obtained oxalate melts with decomposition at 198C Analysis of the oxalate [2(COOl-l) 2 H calculated 52.53 6.52 7.35 found 52.71 6.59 7.00

The following examples 16 to 19 illustrate pharmaceutical compositions according to this invention.

for one capsule -contmued EXAMPLE 17 1& Active ingredient of formula 1 200 mg Potato starch mg Lactose 80 mg Starch sodium glycollate 30 mg Colloidal silica 15 mg Magnesium stearate 5 mg l-{ydroxy propylcellulose 4 mg Stearic acid 2 mg for one tablet EXAMPLE l8 PILLS Core: Active ingredient of formula 1 50.0 mg Lactose 67.5 mg Microcrystalline cellulose 32.0 mg Starch sodium glycollate 8.2 mg Colloidal silica 0.4 mg Magnesium stearate 0.9 mg Coating Shellac 1.0 mg Sandarac 0.2 mg Castor oil 0.3 mg Gum arabic 7.0 mg Talc 11.2 mg Corn starch 1.0 mg Titanium oxide 1.3 mg Dyestuff 4.0 mg Sucrose 142.8 mg White waX/carnauba wax 0.2 mg

for one pill EXAMPLE 19 Solution for perfusion Active ingredient of formula I 200 mg Anhydrous sodium sulfite 60 mg Anhydrous sodium metabisulfite mg Sodium chloride 1.7 mg Water for injection ad 200 ml We claim: 1. A derivative of 1,4-benzodioxan of the general formula:

in which n 1 or 2, X represents two hydrogen atoms or one oxygen atom, R and R represent each a lower alkyl group or form together with the attached nitrogen atom a nitrogenous heterocyclic ring selected from the group consisting of piperidino and pyrrolidino, with the priviso that R may also represent hydrogen and A represents a phenyl or 2-pyridyl group, or a pharmaceutically acceptable acid addition salt of said compound of formula (I).

2. A derivative of 1,4-benzodioxan according to claim 1, in which A represents a phenyl group or a pharmaceutically acceptable acid addition salt thereof.

3. A derivative of 1,4-benzodioxan according to claim 1, in which X represents two hydrogen atoms or a pharmaceutically acceptable acid addition salt thereof.

4. A derivative of 1,4-benzodioxan according to claim 1, in which X represents one oxygen atom or a pharmaceutically acceptable acid addition salt thereof.

8. Z-[N-(meth laminopropionyl)-N-phenylaminomethyl]-1,4-benzo ioxan, or a pharmaceutically acceptable acid addition salt thereof.

9. 2- N-( ethylamino propionyl )-N-phenylaminomethyl]-l,4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof.

1 0, 2-[ N-( B-dimethylaminopropionyl )-N- phenylaminometh l]-l,4-benzodioxan, or a pharmaceutically accepta 1e acid addition salt thereof.

1 1. 2-[ N-( y-diethylaminopropyl N-( Z-pyridyl) 1,4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof. 

1. A DERIVATIVE OF 1,4-BENZODIOXAN OF THE GENERAL FROMULA:
 2. A derivative of 1,4-benzodioxan according to claim 1, in which A represents a phenyl group or a pharmaceutically acceptable acid addition salt thereof.
 3. A derivative of 1,4-benzodioxan according to claim 1, in which X represents two hydrogen atoms or a pharmaceutically acceptable acid addition salt thereof.
 4. A derivative of 1,4-benzodioxan according to claim 1, in which X represents one oxygen atom or a pharmaceutically acceptable acid addition salt thereof.
 5. 2-(N-( Beta -diethylaminoethyl)-N-phenylaminomethyl)-1,4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof.
 6. 2-(N-( gamma -diethylaminopropyl)-N-phenylaminomethyl)-1,4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof.
 7. 2-(N-(methylaminoacetyl)-N-phenylaminomethyl)-1,4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof.
 8. 2-(N-(methylaminopropionyl)-N-phenylaminomethyl)-1,4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof.
 9. 2-(N-(ethylaminopropionyl)-N-phenylaminomethyl)-1,4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof.
 10. 2-(N-( Beta -dimethylaminopropionyl)-N-phenylaminomethyl)-1, 4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof.
 11. 2-(N-( gamma -diethylaminopropyl)-N-(2-pyridyl))-1,4-benzodioxan, or a pharmaceutically acceptable acid addition salt thereof. 